Liver fibrosis is the result of a complex interplay among different cell types. It is characterized by the recruitment of inflammatory cells in response to chronic injury and by the activation of hepatic stellate cells (HSCs), leading to the accumulation of extracellular matrix. Steatosis is commonly coexisting with hepatic inflammation and hepatocellular injury. Increased oxidative stress is a common factor in all chronic liver diseases leading to fibrosis, regardless of their etiology. Injured hepatocytes, HSCs, and infiltrating inflammatory cells are major sources of reactive oxygen species (ROS). Indeed, the oxidative stress will induce the recruitment of inflammatory cells and the activation of HSCs. Therefore, in a chronic liver injury context, a vicious circle of hepatocyte damage, ROS production, HSC activation, and inflammatory cell recruitment will occur, amplifying the fibrogenic answer to injury.
Means for an effective treatment for liver fibrotic diseases, such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), are still insufficient. No treatment is established for patient with NASH, and several therapeutic options are tested in clinical trial (Vuppalanchi R and Chalasani N, Hepatology 2009, 49(1): 306-317; Dowman J. K et al., Q. J. Med. 2010, 103(2):71-83). These studies involve the use of many different families of chemical compounds (fibrates, thiazolidinediones, biguanides, statins, cannabinoids) and therapeutic targets (nuclear receptors, angiotensin receptors, cannabinoid receptors, HMG-CoA reductase). Recently, studies involving thiazolidinediones (rosiglitazone and pioglitazone) have shown that these drugs may improve liver condition but treatment with these drugs is not without undesired effects such as higher risks of congestive cardiac failure and osteoporosis, as well as weight gain with psychological effects on the patient (Dowman J. K et al., op. cit.; Shiri-Sverdlov R et al., J. Hepatol. 2006, 44: 732-41; Neuschwander-Tetri et al., Hepatology 2003, 38:1008-1017). Clinical trials involving the administration of cannabinoids have raised the concern of neuropsychiatric disruption (Vuppalanchi R and Chalasani N, op. cit.). Other therapies currently ongoing are seeking to assess in NASH drugs as antioxidants but none of these treatments has yet showed convincing results (Nelson A et al., J. Clin. Gastroenterol. 2009, 43: 990-994). Candidates for the treatment of liver diseases are disclosed in WO 2011/064350 and US 2013/108573. There is still a need, however, for compounds which are suitable for the treatment of liver diseases, in particular for compounds which may target the several components of fibrotic process such as steatosis, inflammation and collagen deposition and are devoid of the side effects observed with the drugs currently under evaluation.
Chronic kidney disease (CKD), also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. CKD has its general meaning in the art and is used to classify numerous conditions that affect the kidney, destruction of the renal parenchyma and the loss of functional nephrons or glomeruli. It should be further noted that CKD can result from different causes, but the final pathway remains renal fibrosis. Examples of etiology of CKD include, but are not limited to, cardiovascular diseases, hypertension, diabetes, glomerulonephritis, polycystic kidney diseases, and kidney graft rejection. Renal fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the common manifestation of a wide variety of chronic kidney diseases. The pathogenesis of renal fibrosis is, in essence, a monotonous process that is characterized by an excessive accumulation and deposition of extracellular matrix (ECM) components. Renal fibrosis is a progressive process that ultimately leads to end-stage renal failure, a devastating disorder that requires dialysis or kidney transplantation. However, there is no specific treatment unequivocally shown to slow the worsening of chronic kidney disease. Injury to the kidney is associated with release of cytokines/growth factors such as TGF-β, epidermal growth factor (EGF), and platelet derived growth factor (PDGF) by damaged or infiltrating cells. An increase in production of TGF-β is one of the most important mechanisms in the pathogenesis of renal fibrogenesis. TGF-β1 stimulates fibroblast cell activation and induces matrix expression through its interaction with TGF-β receptors, which are mainly composed of two protein families—type I (TβRI) and type II (TβRII) receptors. TGF-β1 binds to TβRII, which results in TβRI recruitment to form a heteromeric TGF-β receptor complex. The complex phosphorylates and activates Smad2 and Smad3, the two major Smads that mediate the profibrotic events. Other signaling pathways such as extracellular regulated kinase 1/2 (ERK1/2) can also be activated in response to TGF-β receptor activation. Activated ERK1/2 contributes to tubular cell apoptosis in the obstructive kidney. Since activation of TGF-β signaling is considered to be the major mechanism that directly promotes fibroblast activation and fibrosis progression, therapeutic intervention of this pathway could be considered as a strategy to halt or prevent renal fibrosis. Candidates for the treatment of CKD are disclosed in WO 2012/159107 and WO 2014/013005. There is still a need, however, for compounds which are suitable for the treatment of CKD.
Lung fibrotic remodelling occurs in pulmonary disease conditions such as acute respiratory distress syndrome, chronic obstructive pulmonary disease and asthma. Pulmonary fibrosis is characterised by the excessive deposition of extracellular matrix in the interstitium, resulting in respiratory failure. Pulmonary fibrosis can be caused by a number of different conditions, including sarcoidosis, hypersensitivity pneumonitis, collagen vascular disease, and inhalant exposure. In a significant number of patients, no underlying cause for the pulmonary fibrosis can be found. These conditions of unknown etiology have been termed idiopathic interstitial pneumonias. The most common form of idiopathic interstitial pneumonia is idiopathic pulmonary fibrosis (IPF). The primary histopathologic finding of IPF is that of usual interstitial pneumonia with temporal heterogeneity of alternating zones of interstitial fibrosis with fibroblastic foci (i.e., newer fibrosis), inflammation, honeycomb changes (i.e., older fibrosis), and normal lung architecture (i. e., no evidence of fibrosis). Candidates for the treatment of IPF are disclosed in WO 2004/103296. Candidates for the treatment of pulmonary fibrotic disorders are disclosed in WO 2009/149188. Recently, studies involving thiazolidinediones such as rosiglitazone have shown that these drugs may improve pulmonary fibrosis but treatment with these drugs is not without undesired effects such as higher risks of congestive cardiac failure (Kung J et al., Expert Opin. Drug Saf. 2012, 11(4):565-579). Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) has anti-fibrotic properties and is approved in Europe and Japan for the treatment of IPF. There is still a need, however, for alternative compounds which are suitable for the treatment of pulmonary fibrotic disorders.
Fibrotic disorders are characterized by abnormal and excessive deposition of collagen and other extracellular matrix (ECM) components in various tissues. Although their aetiology is quite diverse, the presence of ECM-producing fibroblasts displaying an activated phenotype in the affected tissues is typical of fibrotic diseases. Fibroblast activation is characterized by a marked increase in the transcriptional activity of the genes encoding type I and type III collagens and fibronectin, initiation of the expression of alpha-smooth muscle actin (α-SMA), and the reduction of ECM degradative activities. The most frequent systemic fibrotic disorder is systemic fibrosis which is a rare chronic disease of unknown cause. It is a clinically heterogeneous, systemic disorder which affects the connective tissue of the skin, internal organs and the walls of blood vessels. It is characterized by alterations of the microvasculature, disturbances of the immune system and by massive deposition of collagen and other matrix substances in the connective tissue. Basic functions of various cell types (endothelial cells, T-lymphocytes, monocytes, fibroblasts, mast cells) as well as the production and effects of cytokines, growth factors, and adhesion molecules are known to be involved in the development of this disease. Systemic fibrosis is often referred to as scleroderma. The spectrum of sclerodermatous diseases comprises a wide variety of clinical entities such as morphea (patchy, linear, and generalized), pseudo-scleroderma and the overlap-syndromes with similar cutaneous and histopathologic manifestations. In addition, the complex pathophysiology of systemic fibrosis, involving genetic factors, environmental factors, vascular and immune system functions, as well as fibroblasts and matrix substances, and the complexity of the internal organ involvement, results in scierodermatous diseases often being studied as autoimmune or connective tissue diseases. Therefore, systemic fibrosis has been a challenge for clinicians with regards to diagnostic procedures and therapeutic regimens. Clinical diagnosis of systemic fibrosis often involves attention from several disciplines (e.g. dermatologists, rheumatologists, pulmonologists, nephrologists, and gastroenterologists) and may include invasive procedure such as a biopsy of the fibrotic tissue and/or skin for confirmation. Candidates for the treatment of systemic fibrosis are disclosed in US 2013/0287794 and US 2014/0038956. There is still a need, however, for alternative compounds which are suitable for the treatment of systemic fibrosis.
The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein). Three subtypes of PPARs have been identified:                PPARα, which are mainly expressed in liver, kidney, heart, muscle, adipose tissue and lungs;        PPARγ, which are expressed in virtually all tissues;        PPARδ, which are observed on a variety of tissues/cells notably in the cardiovascular, urinary, respiratory, digestive and musculoskeletal systems.        
PPAR agonists are drugs which act upon the PPARs. They are used for the treatment of symptoms of the metabolic diseases, mainly for lowering triglycerides and blood sugar. PPARα agonists essentially consist of the class of fibrates (e.g. fenofibrate). PPARγ agonists essentially consist of thiazolidinediones (e.g. rosiglitazone and pioglitazone). PPARδ agonists include GW501516, a candidate compound that was eventually discontinued due to safety issues.
PPAR receptors expression is modified in fibrosis diseases. For example, decrease expression of PPARγ has been reproducibly described in skin biopsies, as well as in explanted skin fibroblasts from systemic scleroderma patients (Lakota et al, Arthritis Res. Ther. 2012 May 1; 14(3)). A lower expression of PPARγ was also reported in lung fibroblasts from scleroderma patients (Bogatkevich et al, Pulm. Med. Vol 2012; 2012). PPARγ agonists rosiglitazone and pioglitazone protect rodents from bleomycin-induced skin and lung fibrosis in vivo and prevent activation of profibrotic pathways and processes in vitro in fibroblast cell lines and in primary fibroblasts (Aoki et al, Respiration. 2009; 77(3):311-9; Samah et al, Eur J Pharmacol. 2012 Aug. 15; 689(1-3)). PPARα receptors also modulate the profibrotic response to different stimuli. In the lung, fenofibrate, a specific PPARα agonist, prevented bleomycin-induced fibrosis (Samah et al 2012 op cit). Furthermore, PPARδ agonist GW0742 has been shown to reduce lung inflammation induced by bleomycin instillation in mice (Galuppo et al, Int J Immunopathol Pharmacol. 2010 October-December; 23(4):1033-46).